RESPIRATORY EFFECTS PRODUCED BY MICROINJECTION OF L-GLUTAMATE AND AN UPTAKE INHIBITOR OF L-GLUTAMATE INTO THE CAUDAL SUBRETROFACIAL AREA OFTHE MEDULLA

The purposes of our study were to determine the type of respiratory ch anges that would occur when either an excitatory amino acid receptor a gonist or an uptake inhibitor was administered into the caudal subretr ofacial area. This was done by microinjecting either L-glutamate or L- pyrrolidine-2,4-dicarboxylate (L-trans-2,4-PDC) into the caudal subret rofacial area while monitoring tidal volume, respiratory rate, mean ar terial blood pressure and heart rate. Bilateral microinjection of 2.5 nmol of L-glutamate into the caudal subretrofacial area produced apnea in eight of eight animals tested, and the duration of apnea was 27 +/ - 2 s. To determine the type of L-glutamate receptor responsible for m ediating the apneic response, antagonists of the N-methyl-D-aspartate (NMDA) and non-NMDA receptor, namely, 3-[(RS)-carboxypiperazin-4-yl]-p ropyl-phosphonic acid (CPP), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively, were tested. Neither antagonist in doses that bl ocked NMDA (in the case of CPP) and amino-3-hydroxy-5-methyl-isoxazole -4-propionic acid (AMPA) (in the case of CNQX) blocked apnea elicited by L-glutamate. In addition, kynurenic acid, an antagonist of NMDA and non-NMDA ionotropic receptors, failed to block the effect of L-glutam ate. Microinjection of the metabotropic receptor agonist drug, trans-L -1-amino-1,3-cyclopentone-dicarboxylic acid (L-trans-ACPD), into the c audal subretrofacial area failed to have any effect on respiratory act ivity. Because of the inability to block the effect of L-glutamate in the caudal subretrofacial area, and the lack of effect of L-trans-ACPD , the data suggest that the apneic response produced by L-glutamate is -mediated by an as yet undefined receptor. Microinjection of the L-glu tamate uptake inhibitor, L-trans-2,4-PDC, was found to produce apnea. Using the dose of 0.5 nmol of L-trans-2,4-PDC, we examined the type of excitatory amino acid receptor that mediated the response. Neither pr etreatment with the NMDA receptor antagonist, CPP, nor the non-NMDA re ceptor antagonist, CNQX, affected L-trans-2,4-PDC-induced apnea. Howev er, combined use of these two antagonists prevented L-trans-2,4-PDC-in duced apnea. These data suggest that the effect of synaptically releas ed exitatory amino acid at the caudal subretrofacial area on breathing is apnea, and that this effect is mediated by simultaneous activation of both NMDA and non-NMDA ionotropic receptors.